Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Abstract

Epidermal growth factor receptor (EGFR) mutations were first identified as driver oncogenes in non-small-cell lung cancers (NSCLCs) in 2004 by three separate independent groups (1-3), and originally thought to consistent of only inframe deletions, insertions (i.e., indels) or point mutations within exons 18 to 21 of the kinase domain of EGFR (4). The most abundant EGFR mutations are deletions/indels (around amino-acid residues 747 to 752) of exon 19 (these account for ~45% of all EGFR mutations, with the most common delE746_A750) and the exon 21 point mutation L858R mutation (~35% of all EGFR mutations). Inhibition of mutant EGFR in preclinical models through tyrosine kinase inhibitors (TKIs) unsettles the intracellular signaling cascade, generating cell cycle arrest and apoptosis (5). In the clinic, the 1 st generation EGFR TKIs gefitinib and erlotinib, both reversible ATP mimetics with a favorable therapeutic window in relation to the wild-type (WT) EGFR (4,6), induce overall response rate (ORR), EditorialKinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements that comprehensive molecular profiling may be necessary to maximize the identification of all cases that can benefit from precision oncology.

Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

“…In our study, we reported that EGFR-KDDs comprised 0.12% of all NSCLCs and 0.24% of all EGFR aberrations, including the canonical KDD rearrangements involving exons 18-25 and uncommon rearrangements, such as duplications of exons 14-26 and exons 17-25 that have not previously been described. The frequencies of such rearrangements were slightly higher than the previously reported statistics of 0.07% of lung cancers (N = 7,200) reported by Gallant et al 6 and 0.2% of the EGFR-positive cohort (N = 1,510) reported by Costa et al 10 . The higher frequency observed in our study is likely because EGFR mutations are more common in NSCLCs of ethnic Chinese individuals, compared to Caucasians.…”

“…The frequencies of such rearrangements were slightly higher than the previously reported statistics of 0.07% of lung cancers ( N = 7,200) reported by Gallant et al . and 0.2% of the EGFR ‐positive cohort ( N = 1,510) reported by Costa et al …”

Pitfalls in diagnosis with the use of circulating tumor‐derived epidermal growth factor receptor mutations in lung cancer harboring pretreatment T790M

“…Another important finding from this study is that osimertinib treatment was shown to have anti‐tumor activity against a lung cancer harboring both L858R and pretreatment T790M mutations, whereas afatinib was not effective. The in vitro anti‐tumor activity of EGFR‐TKIs varies with the kind of EGFR mutation . Clinically available EGFR‐TKIs, with the exception of osimertinib, are all less effective against cell lines carrying T790M, while the existence of more than 25% of cells harboring T790M has been shown to strongly decrease the in vitro anti‐tumor activity of erlotinib .…”

“…Mutations resistant to EGFR‐TKIs, such as T790M and exon 20 insertions, are in part derived from pre‐existing subclones before treatment . The anti‐tumor activity of EGFR‐TKIs varies with the kind of EGFR mutation, and the results of ctDNA assay may thus influence the choice of EGFR‐TKI . However, whether this assay can detect all components of complex EGFR mutations in the same tumor is undetermined.…”

“…3 The anti-tumor activity of EGFR-TKIs varies with the kind of EGFR mutation, and the results of ctDNA assay may thus influence the choice of EGFR-TKI. 4,5 However, whether this assay can detect all components of complex EGFR mutations in the same tumor is undetermined. We herein report a case of lung adenocarcinoma containing both L858R and pretreatment T790M, known as de novo T790M, in which the ctDNA assay detected only L858R.…”